Live-attenuated SIV strains provide an important model to study cellular and viral determinants that contribute to disease development and they also provide a unique tool to study mechanisms leading to protective immunity. We focused our work on the viral Rev protein, a key regulatory factor, which is conserved among lentiviruses and is essential for promoting the export of the unspliced and intermediate-spliced mRNAs which encode the structural proteins. We postulated that a drastic change in the posttranscriptional regulation may affect the pathogenicity of HIV and SIV. To test this hypothesis, we found that the Rev-RRE regulation could be replaced by the posttranscriptional control mechanisms of the simian type D retroviruses. SRV expression is mediated via the cellular NXF1 (formerly called TAP) protein, which interacts with the viral RNA transport element CTE. Our demonstration that CTE could replace Rev/RRE in HIV and SIV resulting in production of infectious virus in PBMC opened the way for the evaluation of the pathogenicity of Rev-independent viruses in the presence of all other viral proteins using animal models. Studies from my lab have now demonstrated that changes of the posttranscriptional regulation of HIV and SIV profoundly alters the out-come of the infection. We have evidence from infection of neonatal, juvenile, and adult rhesus macaques that Rev-independent SIV strains lack pathogenicity (von Gegerfelt, A. S., et al. J Virol. 73:6159-6165, 1999; von Gegerfelt, A. S., et al. J Virol. 76:96-104, 2002). Our data demonstrate that Rev/RRE regulatory mechanism is required for high levels of virus propagation and that this control mechanism plays an important role in the pathogenicity of SIV. The replacement of Rev/RRE by the NXF1/CTE system provides a novel approach to lower the virulence of a pathogenic lentivirus. The availability of non-pathogenic live-attenuated SIV strains provides us with a unique research tool to dissect pathogenic mechanisms leading to AIDS.